This invention relates to adenosine A-3 receptor agonists, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat for example, ischemia particularly, perioperative myocardial ischemic injury in mammals, including humans.
Mycardial ischemic injury can occur in out-patient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Pharmacological cardioprotection would reduce the incidence and progression of myocardial infarction and dysfunction occurring in these surgical settings (perioperatively). In addition to reducing myocardial damage and improving post-ischemic myocardial function in patients with ischemic heart disease, cardioprotection would also decrease the incidence of cardiac morbidity and mortality due to myocardial infarction and dysfunction in patients xe2x80x9cat riskxe2x80x9d (such as greater than 65 years, exercise intolerant, coronary artery disease, diabetes mellitus, hypertension) that require non-cardiac surgery.
U.S. Pat. No. 5,604,210 discloses the use of certain adenosine type compounds for the prevention or treatment of a brain edema, an intracranial hemorrhage and a cerebral infarction.
U.S. Pat. No. 5,688,774 discloses A3 selective agonists, particularly, adenine compounds having selected substituents at the 2, 6 and 9 positions, and related substituted compounds, particularly those containing substituents on the benzyl and/or uronamide groups as agents which activate the A3 receptor.
U.S. Pat. No. 5,773,423 discloses N6-benzyladenosine-5xe2x80x2-N-uronamide and related substituted compounds, particularly those containing substituents on the benzyl and/or uronamide groups, and modified xanthine ribosides for the activation of the A3 adenosine receptor.
J. Med. Chem. 1994, 37, 636-646, xe2x80x9cStructure-Activity Relationships of N6-Benzyladenosine-5xe2x80x2-uronamides as A3-Selective Agonistsxe2x80x9d discloses the synthesis of adenosine analogues modified at the 5xe2x80x2-position as uronamides and/or as N6-benzyl derivatives which are potentially useful as pharmacological and biochemical probes for A3 receptors.
J. Med. Chem. 1995, 38, 1174-1188, xe2x80x9cSearch for New Purine- and Ribose-Modified Adenosine Analogues as Selective Agonists and Antagonists at Adenosine Receptorsxe2x80x9d, discloses that the binding affinities at rat A1, A2a, and A3 adenosine receptors of a wide range of derivatives of adenosine have been determined. In particular, 3xe2x80x2-xcex2-amino compounds were found to have no activity.
J. Med. Chem. 1995, 38, 1720-1735, xe2x80x9cStructure-Activity Relationships of 9-Alkyladenine and Ribose-Modified Adenosine Derivatives at Rat A3 Adenosine Receptorsxe2x80x9d discloses the synthesis of 9-alkyladenine derivatives and ribose-modified N-benzyladenosine derivatives as leads for the development of antagonists for the rat A3 adenosine receptor.
U.S. Pat. No. 5,817,760 discloses recombinant human adenosine receptors A1, A2a, A2b, and A3 which were prepared by cDNA cloning and polymerase chain reaction techniques. The recombinant adenosine receptors can be utilized in an assay to identify and evaluate entities that bind to or enhance binding to adenosine receptors.
Thus, while there has been some progress in this field of art, there is clearly a need and a continuing search in this field of art for treatments for perioperative myocardial ischemia.
This invention is directed to compounds of Formula I 
prodrugs thereof and pharmaceutically acceptable salts of said compounds and of said prodrug, wherein
X is oxy, methylene or thio;
Y is CH or N;
Z is H, (C1-C4)alkyl, (C1-C4)alkyloxy, trifluoromethyl or halo;
R1 is hydroxymethyl, (C1-C3)alkoxymethyl, (C3-C5)cycloalkoxymethyl, carboxy, (C1-C3)alkoxycarbonyl, (C3-C5)cycloalkoxycarbonyl, 1,1-aminoiminomethyl, 1,1-(mono-N- or di-N,N-(C1-C4)alkylamino)iminomethyl, 1,1-(mono-N- or di-N,N-(C3-C5)cycloalkylamino)iminomethyl, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C3-C5)cycloalkylaminocarbonyl or N-(C1-C4)alkyl-N-(C3-C5)cycloalkylaminocarbonyl;
R2 is H, (C1-C3)alkyl or (C3-C5)cycloalkyl;
R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl;
D is oxy, thio, NH, (C1-C6)alkyloxy, (C1-C6)alkylthio or (C1-C6)alkylamino;
G is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; wherein said G is optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethoxy, nitro, cyano, (C3-C6)cycloalkyl, hydroxy or (C1-C3)alkoxy or
G is cyano, (C1-C4)alkoxycarbonyl, (C3-C5)cycloalkoxycarbonyl, C(O)NR4R5, C(S)NR4R5, C(NH)NR4R5, C(N(C1-C3)alkyl)NR4R5 or C(N(C3-C10)cycloalkyl)NR4R5;
R4 is a bond, H, (C1-C10)alkyl, hydroxy, (C1-C10)alkoxy, (C3-C10)cycloalkoxy or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring or a bicyclic ring with optional (C1-C3) bridge (e.g., adamantane) optionally linked through (C1-C3)alkyl, said bicyclic ring or bridged bicyclic ring optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen wherein said (C1-C10)alkyl, (C1-C10)alkoxy, (C3-C10)cycloalkoxy or R4 ring(s) is optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, nitro, cyano, (C3-C5)cycloalkyl, hydroxy or (C1-C3)alkoxy;
R5 is a bond, H, (C1-C10)alkyl or (C1-C10)cycloalkyl; or
R4 and R5 taken together with the nitrogen to which they are attached form a fully saturated or partially unsaturated four to nine membered ring, said ring optionally bridged, optionally having one to three additional heteroatoms selected independently from oxygen, sulfur and nitrogen, said ring optionally mono- or di-substituted independently with oxo, hydroxy, (C1-C6)alkoxy, (C1-C8)alkyl, amino, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C3-C5)cycloalkylaminocarbonyl, N-(C1-C4)alkyl-N-(C3-C5)cycloalkylaminocarbonyl, mono-N- or di-N,N-(C1-C4)alkylamino, mono-N- or di-N,N-(C3-C5)cycloalkylamino, N-(C1-C4)alkyl-N-(C3-C5)cycloalkylamino, formylamino, (C1-C4)alkylcarbonylamino, (C3-C5)cycloalkylcarbonylamino, (C1-C4)alkoxycarbonylamino, N-(C1-C4)alkoxycarbonyl-N-(C1-C4)alkylamino, (C1-C4)sulfamoyl, (C1-C4)alkylsulfonylamino, (C3-C5)cycloalkylsulfonylamino or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally linked through (C1-C3)alkyl, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen, optionally mono or di-substituted with halo, trifluoromethyl, trifluoromethoxy (C1-C3)alkyl or (C1-C3)alkoxy.
A preferred group of compounds, designated the A Group, contains those compounds having the Formula I as shown above wherein
X is oxy;
Y is N;
Z is H;
R1 is (C1-C8)alkylcarbamoyl;
R2 is H;
R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl;
D is oxy, thio, (C1-C6)alkyloxy or (C1-C6)alkylthio;
G is phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, pyridinazinyl, tetrazolyl, isothiazolyl, thiophenyl, furyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, pyrrolyl, indolyl, naphthalenyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl wherein said G is optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl or (C1-C3)alkoxy; and
pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the A Group of compounds, designated the B Group, contains those compounds wherein
R1 is methylcarbamoyl;
R3 is halo;
D is (C1-C6)alkoxy;
G is phenyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, pyrrolyl wherein said G is optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl, trifluoromethoxy or (C1-C3)alkoxy; and pharmaceutically acceptable salts thereof
A group of compounds which is preferred among the B Group of compounds, designated the C Group, contains those compounds wherein
D is (C1-C2)alkoxy;
G is phenyl, thiazolyl, oxazolyl, isoxazolyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl or morpholinyl wherein said G is optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl or (C1-C3)alkoxy; and pharmaceutically acceptable salts thereof.
Especially preferred compounds within the B Group of compounds are compounds wherein
a. R3 is chloro;
D is methyleneoxy; and
G is phenyl,
b. R3 is chloro;
D is methyleneoxy; and
G is 3-furanyl,
c. R3 is chloro;
D is methyleneoxy; and
G is 2-furanyl,
d. R3 is chloro,
D is methyleneoxy; and
G is 2-thiazolyl,
e. R3 is chloro;
D is methyleneoxy; and
G is 5-(3-methylisoxazolyl); and the pharmaceutically acceptable salts of said compounds.
Especially preferred compounds of this invention are the compounds (2S,3S,4R,5R)3-amino-5-[6-(2-benzyloxy-5-chloro-benzylamino)-purin-9-yl]-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide, (2S,3S,4R,5R)3-amino-5-{6-[5-chloro-2-(furan-3-ylmethoxy)benzylamino]-purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide, (2S,3S,4R,5R)3-amino-5-{6-[5-chloro-2-(furan-2-ylmethoxy)benzylamino] purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide, (2S,3S,4R,5R)3-amino-5-{6-[5-chloro-2-(thiazol-2-ylmethoxy)-benzylamino]-purin-9yl}-4-hydroxy-tetrahydrofuran-2-carboxylic acid methylamide, (2S,3S,4R,5R)3-amino-5-{6-[5-chloro-2-(3-methylisoxazol-5-ylmethoxy)benzylamino]purin-9-yl}-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide, and pharmaceutically acceptable salts of said compounds.
A preferred group of compounds, designated the D Group, contains those compounds having the Formula I as shown above wherein
X is oxy;
Y is N;
Z is H;
R1 is (C1-C6)alkylcarbamoyl;
R2 is H;
R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl;
D is (C1-C6)alkyloxy or (C1-C6)alkylthio;
G is C(O)NR4R5 or C(S)NR4R5 
wherein R4 and R5 taken together with the nitrogen to which they are attached form a fully saturated four to nine membered ring, optionally having one to three additional heteroatoms selected independently from oxygen, sulfur and nitrogen, said ring optionally mono- or di-substituted independently with oxo, (C1-C6)alkoxy, (C1-C8)alkyl, amino, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C3-C5)cycloalkylaminocarbonyl, N-(C1-C4)alkyl-N-(C3-C5)cycloalkylaminocarbonyl, mono-N- or di-N,N-(C1-C4)alkylamino, mono-N- or di-N,N-(C3-C5)cycloalkylamino or N-(C1-C4)alkyl-N-(C3-C5)cycloalkylamino, formylamino, (C1-C4)alkylformylamino, (C3-C5)cycloalkylformylamino, sulfamoyl, (C1-C4)alkylsulfonylamino, (C3-C5)cycloalkylsulfonylamino or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally linked through (C1-C3)alkyl, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and pharmaceutically acceptable salts thereof.
A preferred group of compounds which is preferred among the D Group of compounds, designated the E Group, contains those compounds wherein
R1 is methylcarbamoyl;
R3 is halo;
D is (C1-C2)alkoxy;
G is C(O)NR4R5 or C(S)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperidinyl, piperazinyl, morpholinyl, azetidinyl or pyrrolidinyl said ring optionally mono- or di-substituted independently with oxo, hydroxy, (C1-C6)alkoxy, (C1-C8)alkyl, amino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C3-C5)cycloalkylaminocarbonyl, N-(C1-C4)alkyl-N-(C3-C5)cycloalkylaminocarbonyl, mono-N- or di-N,N-(C1-C4)alkylamino, mono-N- or di-N,N-(C3-C5)cycloalkylamino or N-(C1-C4)alkyl-N-(C3-C5)cycloalkylamino, formylamino, (C1-C4)alkylformylamino, (C3-C5)cycloalkylformylamino, sulfamoyl, (C1-C4)alkylsulfonylamino, (C3-C5)cycloalkylsulfonylamino or
a partially saturated, fully saturated or fully unsaturated four to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; and
pharmaceutically acceptable salts thereof.
A preferred group of compounds which is preferred among the E Group of compounds, designated the F Group, contains those compounds wherein
G is C(O)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl said ring optionally mono- or di-substituted independently with hydroxy, oxo, (C1-C6)alkoxy, (C1-C8)alkyl, amino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C1-C4)alkylamino, or a partially saturated, fully saturated or fully unsaturated four to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; and pharmaceutically acceptable salts thereof.
Especially preferred compounds within the F Group of compounds are compounds wherein
a. R3 is chloro;
D is methyleneoxy;
G is C(O)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperazinyl substituted in the four position with methyl,
b. R3 is chloro;
D is methyleneoxy;
G is C(O)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperazinyl,
c. R3 is chloro;
D is methyleneoxy;
G is C(O)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperidinyl substituted in the four position with N,N-dimethylamino,
d. R3 is chloro;
D is methyleneoxy;
G is C(O)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperidinyl substituted in the four position with piperidin-1-yl,
e. R3 is chloro;
D is methyleneoxy;
G is C(O)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperidinyl substituted in the four position with methylamino, and pharmaceutically acceptable salts of said compounds.
A preferred group of compounds, designated the G Group, contains those compounds having the Formula I as shown above wherein
X is oxy;
Y is N;
Z is H;
R1 is (C1-C6)alkylcarbamoyl;
R2 is H;
R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl;
D is (C1-C6)alkyloxy or (C1-C6)alkylthio;
G is C(O)NR4R5 or C(S)NR4R5;
R4 is H, (C1-C10)alkyl, hydroxy, (C1-C10)alkoxy, (C3-C10)cycloalkoxy or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally linked through (C1-C3)alkyl, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
R5 is H, (C1-C10)alkyl or (C1-C10)cycloalkyl; and pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the G Group of compounds, designated the H Group, contains those compounds wherein
R1 is methylcarbamoyl;
R3 is halo;
D is (C1-C2)alkoxy;
G is C(O)NR4R5 or C(S)NR4R5;
R4 is H, (C1-C10)alkyl, hydroxy, (C1-C10)alkoxy, (C3-C10)cycloalkoxy or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen;
R5 is H, (C1-C10)alkyl or (C1-C10)cycloalkyl; and pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the H Group of compounds, designated the I Group, contains those compounds wherein
G is C(O)NR4R5;
R4 is H, (C1-C10)alkyl, (C3-C6)cycloalkyl, hydroxy, (C1-C10)alkoxy or (C3-C10)cycloalkoxy;
R5 is H, (C1-C10)alkyl or (C3-C10)cycloalkyl; and pharmaceutically acceptable salts thereof.
An especially preferred compound within the I Group of compounds is the compound wherein
R3 is chloro;
D is methyleneoxy;
G is C(O)NR4R5;
R4 is H;
R5 is H; and pharmaceutically acceptable salts thereof.
A preferred group of compounds, designated the J Group, contains those compounds having the Formula I as shown above wherein
D is oxy, thio, (C1-C6)alkyloxy or (C1-C6)alkylthio;
G is phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, isoxazolyl, pyridinazinyl, tetrazolyl, isothiazolyl, thiophenyl, furanyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, pyrrolyl, indolyl, naphthalenyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl wherein said G is optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl or (C1-C3)alkoxy; and
pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the J Group of compounds, designated the K Group, contains those compounds wherein
D is (C1-C6)alkoxy;
G is phenyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrazolyl, pyrrolyl wherein said G is optionally mono-, di- or tri-substituted independently with halo, (C1-C3)alkyl or (C1-C3)alkoxy;
and pharmaceutically acceptable salts thereof.
A preferred group of compounds, designated the L Group, contains those compounds having the Formula I as shown above wherein
D is (C1-C6)alkyloxy or (C1-C6)alkylthio;
G is C(O)NR4R5 or C(S)NR4R5 
wherein R4 and R5 taken together with the nitrogen to which they are attached form a fully saturated four to nine membered ring, optionally having one to three additional heteroatoms selected independently from oxygen, sulfur and nitrogen, said ring optionally mono- or di-substituted independently with oxo, hydroxy, (C1-C6)alkoxy, (C1-C8)alkyl, amino, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C3-C5)cycloalkylaminocarbonyl, N-(C1-C4)alkyl-N-(C3-C5)cycloalkylaminocarbonyl, mono-N- or di-N,N-(C1-C4)alkylamino, mono-N- or di-N,N-(C3-C5)cycloalkylamino or N-(C1-C4)alkyl-N-(C3-C5)cycloalkylamino, formylamino, (C1-C4)alkylformylamino, (C3-C5)cycloalkylformylamino, sulfamoyl, (C1-C4)alkylsulfonylamino, (C3-C5)cycloalkylsulfonylamino or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally linked through (C1-C3)alkyl, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen; and pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the L Group of compounds, designated the M Group, contains those compounds wherein
D is (C1-C2)alkoxy;
G is C(O)NR4R5 or C(S)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperidinyl, piperazinyl, morpholinyl, azetidinyl or pyrrolidinyl said ring optionally mono- or di-substituted independently with oxo, (C1-C6)alkoxy, (C1-C8)alkyl, amino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C3-C5)cycloalkylaminocarbonyl, N-(C1-C4)alkyl-N-(C3-C5)cycloalkylaminocarbonyl, mono-N- or di-N,N-(C1-C4)alkylamino, mono-N- or di-N,N-(C3-C5)cycloalkylamino or N-(C1-C4)alkyl-N-(C3-C5)cycloalkylamino, formylamino, (C1-C4)alkylformylamino, (C3-C5)cycloalkylformylamino, sulfamoyl, (C1-C4)alkylsulfonylamino, (C3-C5)cycloalkylsulfonylamino or a partially saturated, fully saturated or fully unsaturated four to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; and
pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the M Group of compounds, designated the N Group, contains those compounds wherein
G is C(O)NR4R5;
wherein R4 and R5 taken together with the nitrogen to which they are attached form piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl said ring optionally mono- or di-substituted independently with oxo, hydroxy, (C1-C6)alkoxy, (C1-C8)alkyl, amino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylaminocarbonyl, mono-N- or di-N,N-(C1-C4)alkylamino, or a partially saturated, fully saturated or fully unsaturated four to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen; and pharmaceutically acceptable salts thereof.
A preferred group of compounds, designated the O Group, contains those compounds having the Formula I as shown above wherein
D is (C1-C6)alkyloxy or (C1-C6)alkylthio;
G is C(O)NR4R5 or C(S)NR4R5;
R4 is H, (C1-C10)alkyl, hydroxy, (C1-C10)alkoxy, (C3-C10)cycloalkoxy or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally linked through (C1-C3)alkyl, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
R5 is H, (C1-C10)alkyl or (C1-C10)cycloalkyl;
and pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the O Group of compounds, designated the P Group, contains those compounds wherein
D is (C1-C2)alkoxy;
R4 is H, (C1-C10)alkyl, hydroxy, (C1-C10)alkoxy, (C3-C10)cycloalkoxy or a partially saturated, fully saturated or fully unsaturated five to eight membered ring, optionally linked through (C1-C3)alkyl, optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen;
R5 is H, (C1-C10)alkyl or (C1-C10)cycloalkyl; and pharmaceutically acceptable salts thereof.
A group of compounds which is preferred among the P Group of compounds, designated the Q Group, contains those compounds wherein
G is C(O)NR4R5;
R4 is H, (C1-C10)alkyl, (C3-C6)cycloalkyl, hydroxy, (C1-C10)alkoxy or (C3-C10)cycloalkoxy;
R5 is H, (C1-C10)alkyl or (C3-C10)cycloalkyl; and pharmaceutically acceptable salts thereof.
Another aspect of this invention is directed to compounds having the Formula C 
wherein R20 and R21 are each independently (C1-C4)alkyl, H, phenyl, phenyl(C1-C4)alkyl or are joined together to form a piperidinyl, pyrrolidinyl or morpholinyl ring;
R22 and R23 are each independently (C1-C4)alkyl or are joined together to form a 5-6 membered carbocyclic ring; and
R24 is (C1-C4)alkyl, phenyl or phenyl(C1-C4)alkyl, said phenyl or phenyl(C1-C4)alkyl optionally mono-, di, or tri-substituted independently on the phenyl moiety with nitro, halo or trifluoromethyl.
Another aspect of this invention is directed to compounds having the Formula CI 
wherein R20 and R21 are each independently (C1-C4)alkyl, H, phenyl, phenyl(C1-C4)alkyl or are joined together to form a piperidinyl, pyrrolidinyl or morpholinyl ring; and
R24 is (C1-C4)alkyl, phenyl or phenyl (C1-C4)alkyl, said phenyl or phenyl(C1-C4)alkyl optionally mono-, di, or tri-substituted independently on the phenyl moiety with nitro, halo or trifluoromethyl.
Another aspect of this invention is directed to compounds having the Formula CII 
wherein R20 and R21 are each independently (C1-C4)alkyl, H, phenyl, phenyl(C1-C4)alkyl or are joined together to form a piperidinyl, pyrrolidinyl or morpholinyl ring;
R24 is (C1-C4)alkyl, phenyl or phenyl (C1-C4)alkyl, said phenyl or phenyl(C1-C4)alkyl optionally mono-, di, or tri-substituted independently on the phenyl moiety with nitro, halo or trifluoromethyl; and
R25 and R26 are each independently (C1-C4)alkyl or phenyl.
Another aspect of this invention is directed to compounds having the Formula CIII 
wherein R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl.
Especially preferred compounds having Formula CIII as shown above are compounds wherein
a. R3 is trifluoromethyl;
b. R3 is fluoro; and
c. R3 is chloro.
Another aspect of this invention is directed to compounds having Formula CIV 
wherein R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl.
Especially preferred compounds having Formula CIV as shown above are compounds wherein
a. R3 is trifluoromethyl;
b. R3 is fluoro; and
c. R3 is chloro.
Another aspect of this invention is directed to compounds having the Formula CV 
wherein R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl.
Especially preferred compounds having Formula CV as shown above are compounds wherein
a. R3 is trifluoromethyl;
b. R3 is fluoro; and
c. R3 is chloro.
Another aspect of this invention is directed to compounds having the Formula CVI 
wherein R2 is H, (C1-C3)alkyl or (C3-C5)cycloalkyl; and
R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl.
Especially preferred compounds having Formula CVI as shown above are compounds wherein
a. R2 is H; and
R3 is chloro,
b. R2 is H; and
R3 is fluoro,
c. R2 is cyclopropyl; and
R3 is fluoro.
Another aspect of this invention is directed to a method of making a compound of Formula CVII 
wherein T is (C1-C4)alkyl;
R2 is H, (C1-C3)alkyl or (C3-C5)cycloalkyl; and
R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl;
comprising acylating a (C1-C4alkyl)amine with a Formula CVI compound. 
wherein
R2 is H, (C1-C3)alkyl or (C3-C5)cycloalkyl; and
R3 is halo, trifluoromethyl, cyano, (C1-C3)alkyl, (C1-C3)alkyloxy, ethenyl or ethynyl.
A preferred aspect of the above method is wherein
R2 is H or cyclopropyl;
R3 is fluoro, chloro or trifluoromethyl;
and the Formula CVI acid is esterified to a (C1-C6)alkyl ester prior to acylation with the (C1-C4)alkylamine.
An especially preferred aspect of the immediately preceding method is wherein the Formula CVI acid is esterified with an alcohol in the presence of acid at a temperature of ambient to reflux for a period of about 1 hour to about 12 hours.
An especially preferred aspect of the immediately preceding method, is wherein the ester is reacted with the amine at a temperature of about ambient to reflux for about one to about 12 hours in an alcohol solvent.
An especially preferred aspect of the immediately preceding method designated the X method is, wherein the esterification occurs at a temperature of about 50xc2x0 C. and the acylation occurs at a temperature of about 50xc2x0 C.
An especially preferred aspect of the X method is wherein
the alcohol is methanol;
the acid is HCl;
the amine is methylamine;
R2 is H; and
R3 is chloro.
An especially preferred aspect of the X method is wherein
the alcohol is methanol;
the acid is HCl;
the amine is methylamine;
R2 is cyclopropyl; and
R3 is fluoro.
An especially preferred aspect of the X method is wherein
the alcohol is methanol;
the acid is HCl;
the amine is methylamine;
R2 is H; and
R3 is trifluoromethyl.
Another aspect of this invention are methods of treating a mammal (e.g., human) having a disease or condition mediated by an A3 adenosine receptor by administering a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug to the mammal.
Another aspect of this invention is directed to methods of reducing tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) resulting from ischemia or hypoxia comprising administering to a mammal (e.g., a female or male human) in need of such treatment a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Preferred ischemic/hypoxic tissues taken individually or as a group are wherein the ischemic/hypoxic tissue is cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, or intestinal tissue.
An especially preferred ischemic/hypoxic tissue is cardiac tissue.
It is especially preferred that the compounds are administered to prevent perioperative myocardial ischemic injury.
Preferably, the compounds of this invention are administered prophylactically.
The ischemic/hypoxic damage may occur during organ transplantation.
Preferably, the compounds of this invention are administered prior to, during or shortly after, cardiac surgery or non-cardiac surgery (e.g., a three to four day infusion).
In one aspect of this invention a compound of Formula I is administered locally.
A preferred dosage is about 0.001 to 100 mg/kg/day of the Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug. An especially preferred dosage is about 0.01 to 50 mg/kg/day of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) during surgery (e.g., coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA) or any percutaneous transluminal coronary intervention (PTCI), organ transplantation, or other non-cardiac surgeries) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) in patients presenting with ongoing cardiac (acute coronary syndromes, e.g., myocardial infarction or unstable angina) or cerebral ischemic events (e.g., stroke) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to chronic methods of reducing myocardial tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) in a patient with diagnosed coronary heart disease (e.g., previous myocardial infarction or unstable angina) or patients who are at high risk for myocardial infarction (e.g., age  greater than 65 and two or more risk factors for coronary heart disease) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods of preventing ischemic/hypoxic damage comprising the chronic oral administration to a mammal in need of such treatment of a therapeutically effective amount of a compound of Formula I, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating cardiovascular diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating arteriosclerosis comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating arrhythmia comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating angina pectoris comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating cardiac hypertrophy comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating renal diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating diabetic complications comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating restenosis comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating organ hypertrophies or hyperplasias comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating septic shock and other inflammatory diseases (septicemia, endotoxcemia) comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating cerebro ischemic disorders comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating myocardial stunning comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating myocardial dysfunction comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating cerebrovascular diseases comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
Another aspect of this invention is directed to methods for treating organ hypertrophies or hyperplasias comprising administering to a mammal (e.g., a female or male human) a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug.
This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to pharmaceutical compositions for the reduction of tissue damage resulting from ischemia or hypoxia which comprise a therapeutically effective amount of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent.
This invention is also directed to a kit for use by a consumer having or at risk of having a disease or condition resulting from, for example, ischemia or hypoxia which may be ameliorated by an A3 agonist. The kit comprises a) a suitable dosage form such as an injectable parenteral solution particularly adapted for intravenous or intramuscular injection comprising a compound of Formula I; and b) instructions describing a method of using the dosage form to reduce tissue damage resulting from ischemia or hypoxia.
In the above pharmaceutical compositions and methods, preferred Formula I compounds include the preferred groups of compounds described above labeled as Group A-to Group Q.
Yet another aspect of this invention are combinations of a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and other compounds as described below.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising
a first compound, said first compound being a compound Formula I of a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug;
a second compound, said second compound being a cardiovascular agent; and, optionally,
a pharmaceutical carrier, vehicle or diluent.
Another aspect of this invention are methods of reducing tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) resulting from or which could result from ischemia or hypoxia comprising administering to a mammal (e.g., a female or male human)
a. a first compound, said first compound being a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and
b. a second compound, said second compound being a cardiovascular agent
wherein the amounts of the first and second compounds result in a therapeutic effect.
Another aspect of this invention are kits comprising:
a. a compound of Formula I, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b. a cardiovascular agent and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
In the above combination compositions, combination methods and kits, preferably the cardiovascular agents and salts thereof (e.g., agents having a cardiovascular effect) are, for example, xcex2-blockers (e.g., acebutolol, atenolol, bopindolol, labetolol, mepindolol, nadolol, oxprenol, pindolol, propranolol, sotalol), calcium channel blockers (e.g., amlodipine, nifedipine, nisoldipine, nitrendipine, verapamil), potassium channel openers, adenosine, adenosine agonists, sodium-hydrogen exchanger type 1 (NHE-1) inhibitors, ACE inhibitors (e.g., captopril, enalapril), nitrates (e.g., isosorbide dinitrate, isosorbide 5-mononitrate, glyceryl trinitrate), diuretics (e.g., hydrochlorothiazide, indapamide, piretanide, xipamide), glycosides (e.g., digoxin, metildigoxin), thrombolytics (e.g. tPA), platelet inhibitors (e.g., reopro), aspirin, dipyridamol, potassium chloride, clonidine, prazosin, pyruvate dehydrogenase kinase inhibitors (e.g., dichloroacetate), pyruvate dehydrogenase complex activators, biguanides (e.g., metformin) or other adenosine A3 receptor agonists. Other cardiovascular agents include angiotensin II (AII) receptor antagonists, C5a inhibitors, soluble complement receptor type 1 (sCR1) or analogues, partial fatty acid oxidation (PFOX) inhibitors (specifically, ranolazine), acetyl CoA carboxylase activators, malonyl CoA decarboxylase inhibitors, 5xe2x80x2AMP-activated protein kinase (AMPK) inhibitors, adenosine nucleoside inhibitors, anti-apoptotic agents (e.g., caspase inhibitors), monophosphoryl lipid A or analogues, nitric oxide synthase activators/inhibitors, protein kinase C activators (specifically, protein kinase xcex5), protein kinase delta inhibitor, poly (ADP ribose) synthetase (PARS, PARP) inhibitors, metformin (gluconeogenesis inhibitors, insulin sensitizers), endothelin converting enzyme (ECE) inhibitors, endothelin ETA receptor antagonists, (thrombin activated fibrinolytic inhibitor) TAFI inhibitors and Na/Ca exchanger modulators.
Especially preferred NHE-1 inhibitors are [1-(8-bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(6-chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(indazol-7-yl)-5-cyclopropyl-1H-pyrazolecarbonyl]guanidine;
[1-(benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1-methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(5-quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(5-quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine;
[5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1,4-benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(benzotriazol-5-yl)-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(3-chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(5-quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidine;
[5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-4-methylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2,5-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2,3-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-aminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-dimethylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-trifluoromethyl-4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidine;
[5-methyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine;
[5-ethyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidine; and
pharmaceutically acceptable salts thereof.
In the above combination compositions, combination methods and kits preferred Formula I compounds include the preferred groups of compounds described above labeled as Group A to Group Q.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising
a first compound, said first compound being a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug;
a second compound, said second compound being a glycogen phosphorylase inhibitor; and, optionally,
a pharmaceutical carrier, vehicle or diluent.
Another aspect of this invention are methods of reducing tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) resulting from or which could result from ischemia or hypoxia comprising administering to a mammal (e.g., a female or male human)
a. a first compound, said first compound being a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and
b. a second compound, said second compound being a glycogen phosphorylase inhibitor
wherein the amounts of the first and second compounds result in a therapeutic effect.
Another aspect of this invention are kits comprising:
a. a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b. a glycogen phosphorylase inhibitor and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
In the above combination compositions, combination methods and kits preferred Formula I compounds include the preferred groups of compounds described above labeled as Group A to Group Q.
In the above combination compositions, combination methods and kits preferred glycogen phosphorylase inhibitors are
5-chloro-1H-indole-2-carboxylic acid [(1S)((R)hydroxy-dimethylcarbamoyl-methyl)-2-phenyl-ethyl]-amide,
5,6-dichloro-1H-indole-2-carboxylic acid {(1S)-[(R)-hydroxy-(methoxy-methyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide,
5-chloro-1H-indole-2-carboxylic acid {(1S)[(R)-hydroxy-(methoxy-methyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide,
5-chloro-1H-indole-2-carboxylic acid {(1S)((R)-hydroxy-[(2-hydroxy-ethyl)-methyl-carbamoyl]-methyl}-2-phenyl-ethyl)-amide,
5-chloro-1H-indole-2-carboxylic acid {(1S)[(R)-hydroxy-(methyl-pyridin-2-yl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide,
5-chloro-1H-indole-2-carboxylic acid ((1S)-{(R)-hydroxy-[methyl-(2-pyridin-2-yl-ethyl)carbamoyl]-methyl}-2-phenyl-ethyl)-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-3-amide hydrochloride,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-(3-hydroxy-azetidin-1-yl)-3-oxo-propyl]-amide,
5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-isoxazolidin-2-yl-3-oxo-propyl)-amide,
5-chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-(2R)-hydroxy-3-[1,2]oxazinan-2-yl-3-oxo-propyl)-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3S)-hydroxy-pyrrolidin-1-yl)-3-oxo-propyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)benzyl-3-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-oxo-propyl]-amide,
5-chloro-1H-indole-2-carboxylic acid ((1S)benzyl-(2R)-hydroxy-3-morpholin-4-yl-3-oxo-propyl)-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid (2-oxo-2-thiazolidin-3-yl-ethyl)-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-(2-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,
5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide,
5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(3-hydroxyimino-azetidin-1-yl)-2-oxo-ethyl]-amide or
5-chloro-1H-indole-2-carboxylic acid [(1S)benzyl-2-(4-hydroxyimino-piperidin-1-yl)-2-oxo-ethyl]-amide.
This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising
a first compound, said first compound being a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug;
a second compound, said second compound being an aldose reductase inhibitor; and, optionally,
a pharmaceutical carrier, vehicle or diluent.
Another aspect of this invention are methods of reducing tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) resulting from or which could result from ischemia or hypoxia comprising administering to a mammal (e.g., a female or male human)
a. a first compound, said first compound being a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and
b. a second compound, said second compound being an aldose reductase inhibitor
wherein the amounts of the first and second compounds result in a therapeutic effect.
Another aspect of this invention are kits comprising:
a. a Formula I compound, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b. an aldose reductase inhibitor and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
In the above combination compositions, combination methods and kits preferred Formula I compounds include the preferred groups of compounds described above labeled as Group A to Group Q.
In the above combination compositions, combination methods and kits a preferred aldose reductase inhibitor is zopolrestat: 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-.
In the methods of treatment as applied to the combinations described above the following are preferred administration routes, modes, etc.
Preferred ischemic or hypoxic tissues taken individually or as a group are wherein the ischemic/hypoxic tissue is cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, or intestinal tissue.
An especially preferred ischemic or hypoxic tissue is cardiac tissue.
It is especially preferred that the combinations are administered to prevent perioperative myocardial ischemic injury.
Preferably, the combinations of this invention are administered prophylactically.
The ischemic/hypoxic damage may occur during organ transplantation.
Preferably, the combinations of this invention are administered prior to, during and/or shortly after, cardiac surgery or non-cardiac surgery.
In one aspect of this invention the combinations are administered locally.
In one aspect of this inventor myocardial tissue damage is reduced during or after surgery.
In another aspect of this inventor myocardial tissue damage is reduced in patients presenting with ongoing cardiac or cerebral ischemic events.
In yet another aspect of this inventor myocardial tissue damage is reduced by chronic administration of the above combinations in a patient with diagnosed coronary heart disease.
The term xe2x80x9creductionxe2x80x9d is intended to include partial prevention or prevention which, although greater than that which would result from taking no compound or from taking a placebo, is less than 100% in addition to substantially total prevention.
The term xe2x80x9cdamage resulting from ischemia or hypoxiaxe2x80x9d as employed herein refers to conditions directly associated with reduced blood flow or oxygen delivery to tissue, for example due to a clot or obstruction of blood vessels which supply blood to the subject tissue and which result, inter alia, in lowered oxygen transport to such tissue, impaired tissue performance, tissue dysfunction and/or necrosis and/or apoptosis. Alternatively, where blood flow or organ perfusion may be quantitatively adequate, the oxygen carrying capacity of the blood or organ perfusion medium may be reduced, e.g., in hypoxic environment, such that oxygen supply to the tissue is lowered, and impaired tissue performance, tissue dysfunction, and/or tissue necrosis and/or apoptosis ensues.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors which, following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
Exemplary five to six membered aromatic rings optionally having one or two heteroatoms selected independently from oxygen, nitrogen and sulfur are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl and pyrazinyl.
Exemplary partially saturated, fully saturated or fully unsaturated five to eight membered rings optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Further exemplary five membered rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.
Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl and 1,4,2-oxadiazinyl.
Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.
Further exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
Exemplary bicyclic rings consisting of two fused partially saturated, fully saturated or fully unsaturated five and/or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
By alkylene is meant saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene). Of course, such linking moieties may also be referred to as the substituent without the xe2x80x9cenexe2x80x9d suffix (e.g., methyl) as is commonly done by those skilled in the art, and still refer to a linking group.
By halo is meant chloro, bromo, iodo, or fluoro.
By alkyl is meant straight chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By alkoxy is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxygen. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.
As used herein the term mono-N- or di-N,N-(C1-Cx)alkyl . . . refers to the (C1-Cx)alkyl moiety taken independently when it is di-N,N-(C1-Cx)alkyl . . . (x refers to integers).
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term xe2x80x9cpyridylxe2x80x9d means 2-, 3-, or 4-pyridyl, the term xe2x80x9cthienylxe2x80x9d means 2-, or 3-thienyl, and so forth.
The expression xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to nontoxic anionic salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, methanesulfonate and 4-toluene-sulfonate. Where more than one basic moiety exists the expression includes multiple salts (e.g., di-salt). The expression also refers to nontoxic cationic salts such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benethamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
As used herein, the expressions xe2x80x9creaction-inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates of the compounds of this invention are also included.
DMF means N,N-dimethylformamide. DMSO means dimethyl sulfoxide. THF means tetrahydrofuran.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Other features and advantages will be apparent from this description and claims which describe the invention.